We have developed a drug discovery pipeline targeting prion disease, and have been successful in identifying compounds that are effective in a cell-based model of prion disease. Our in vivo studies of these compounds have demonstrated that the efficacy of any anti-prion compound is dependent.on bioactivity and the ability to penetrate the blood-brain-barrier (BBB). We seek funding to expand our promising drug discovery pipeline to quantitate compound concentration in tissue and serum, following oral administration. This ADMET data will identify compounds that can achieve therapeutic concentrations within the CNS. To facilitate these in vivo experiments, we propose to undertake the multi-gram synthesis of any anti-prion compound that warrants in vivo study. Additionally, we have identified some important downstream applications of ADMET data for the design of CNS active anti-prion compounds. This proposed supplement [unreadable] is an important and necessary step in completing the research being conducted in Project 2 (Transgenic Mouse Models for Assessing Treatments of Prion Diseases), of this program project "Novel Therapeutics for Prion Diseases" (AG021601). Additionally, the data generated from this proposal is directly applicable to the ongoing research outlined in AG021601, Projects 3 (Combinatorial Synthesis of Quinacrine Analogs) and 4 (Understanding and Improving Small Molecule Inhibitors of Prion Replication). [unreadable] [unreadable]